Effectiveness of the oxygen reserve index in detecting and preventing hyperoxia in critically ill patients on mechanical ventilation: a randomized controlled trial

Aim To assess the effectiveness of fraction of inspired oxygen (FiO2) titration guided by oxygen reserve index (ORi) in preventing hyperoxia in intensive care unit (ICU) patients receiving mechanical ventilator support. Methods Patients aged 18 years and older who were admitted to a tertiary ICU and required mechanical ventilator support were randomly divided into two groups: the control group (n = 30) and the oxygen saturation (SpO2) +ORi group (n = 30). In the SpO2+ORi group, the goal was to maintain SpO2 between 95% and 98% and ORi at 0.00. In both groups, SpO2, ORi, partial pressure of oxygen (PaO2), partial pressure of carbon dioxide, positive end-expiratory pressure, FiO2, and hemodynamic parameters were recorded every six hours for two consecutive days. Results A very strong positive linear correlation was found between PaO2 and ORi (r = 0.937; P < 0.001). In the ORi+SpO2 group, PaO2 values were significantly lower and decreased with FiO2 titration over time. Severe hyperoxia was observed in 24.8% of the control group and in only 3.3% of the ORi+SpO2 group. When PaO2>120 mm Hg, FiO2>0.40 was found in 83.5% of the control group, and in 40% of the ORi+SpO2 group. Conclusion FiO2 titration guided by ORi+SpO2 effectively prevents hyperoxia and reduces the exposure time to hyperoxia in critically ill patients. Clinicaltrials.gov registration number: NCT05807815.

Oxygen therapy plays a vital role in the treatment of critically ill patients.Mechanical ventilation (MV) support and therapy are routine practices in intensive care units (ICUs).In critically ill patients treated in ICUs, the focus is on the prevention of hypoxia with a liberal use of oxygen (1).However, long-term exposure to iatrogenic hyperoxia and high arterial oxygen tension is common.Arterial hyperoxia is often accepted and normalized in these settings (2)(3)(4).
Recent studies have demonstrated that hyperoxia can be as detrimental as hypoxia, and it directly negatively affects mortality and morbidity (4)(5)(6)(7).In critically ill patients, hyperoxia can lead to lung injury in addition to barotrauma caused by mechanical ventilation support (2).High arterial oxygen tension has potential risks, including hypercapnia, atelectasis, acute tracheobronchitis, pneumonia, acute hyperoxic acute lung injury, acute respiratory distress syndrome (ARDS), systemic vasoconstriction, and cardiac output depression (1,5,8,9).Therefore, avoiding hyperoxia is essential for preventing ventilator-induced lung injury, and it should be considered as part of lung-protective ventilation strategies.
Two methods that have been used for oxygen monitoring -pulse oximetry and arterial blood gas analysis -have not been entirely successful in hypoxia detection.Pulse oximetry, which is used noninvasively to help ensure optimal oxygenation, is alone not sufficient to monitor partial pressure of oxygen (PaO 2 ) levels in a hyperoxic range (10,11).Arterial blood gas analysis, considered the gold standard for oxygen monitoring and detecting hyperoxia, also has several disadvantages (11,12).Therefore, to achieve optimum oxygenation, noninvasive tools should be used to detect hyperoxia (10,11).The Oxygen Reserve Index (ORi, Masimo Corp., Irvine, CA, USA) is a continuous, noninvasive variable that can guide clinicians in detecting moderate hyperoxia (PaO 2 ranging from approximately 100-200 mm Hg).Continuous noninvasive monitoring of ORi in intensive care can be used to detect and prevent hyperoxia.ORi is a unitless index that varies between 0.00 (no oxygen reserve) and 1.00 (maximum reserve) according to the real-time oxygenation reserve status.Although ORi is not a direct measure of PaO 2 , it is a dimensionless variable that is usually obtained in SpO 2 >98% and is directly related to oxygen reserve (10,11,13,14).
To achieve optimal oxygenation (neither hypoxia nor hyperoxia), the fraction of inspired oxygen (FiO 2 ) titration can be guided by using SpO 2 and ORi together.However, considering the duration of intensive care unit stay and the mean anesthesia duration, critically ill patients in ICUs are often exposed to hyperoxia for longer periods of time.Therefore, not only the severe hyperoxia level but also FiO 2 titration is important in critically ill patients in ICUs.Despite numerous studies focusing on the prevention of hypoxia in the ICU, there are limited investigations into the noninvasive detection of hyperoxia and its prevention through FiO 2 titration.Thus, this study aimed to determine the incidence of hyperoxia in patients receiving mechanical ventilator support in the ICU and to investigate the effectiveness of ORi+SpO 2 -guided FiO 2 titration in preventing hyperoxia.

Study design
This randomized controlled study was conducted in the tertiary ICU of the Health Sciences University, Izmir Tepecik Training and Research Hospital.The tertiary ICU has a capacity of 41 beds and is staffed by physicians with at least four years of experience in full-time intensive care.All clinicians participating in the study had advanced intensive care training and were familiar with the clinic's current protocols, with at least two experienced doctors covering the night shifts each day.In the enrollment process, 102 patients were assessed for study eligibility.The assessment was carried out between March 1, 2021 and March 1, 2023.By choosing this timeframe, we took into account changes in the admission of patients and ensured transparency in the recruitment process.The study included patients who were hospitalized during this period and met the eligibility criteria.This study was approved by the Institutional Review Board and Ethics Committee of the Health Sciences University İzmir Tepecik Training and Research Hospital, and written informed consent was obtained from patients' family members.

Setting
Patients were randomly assigned to the control group or the SpO 2 +ORi group (Figure 1).A computer-generated randomization table (https://www.randomization.com)was used for patient assignment.Group allocations were enclosed in sequentially numbered, sealed, opaque envelopes.Randomization of patients as identified in the sealed envelopes was performed by the first investigator just before the study protocol was applied.The second investigator adjusted the FiO 2 according to the allocated group, after being informed about the allocation groups by the first investigator.The third investigator, who was blinded to the group allocation, recorded all data and conducted the data analysis.
In the control group, only observation was performed, and ORi data were recorded without informing the intensive care physician.Oxygen therapy and FiO 2 values were determined based on the clinical practices of the ICU physicians.
No restrictions were applied to the mechanical ventilator mode in either group, and all adjustments were made by physicians as per the hospital's ICU policy, with nurses only being able to make suggestions.

Data collection
In addition to routine monitoring methods, ORi and blood gas analysis were used to monitor PaO 2 and PaCO 2 levels.ORi values were assessed with a Radical-7® device (Masimo Corp.) Demographic data were also recorded.Both groups were monitored every six hours for two consecutive days.Patient data from Radical-7® (SpO 2 and ORi), mean arterial pressure (MAP), heart rate (HR), arterial blood gas measurements (PaO 2 and PaCO 2 ), positive end-expiratory pressure (PEEP), and FiO 2 values in MV were recorded.In addition, based on the PaO 2 levels from arterial blood gas measurements, the patients were classified into three categories: normoxive (80-100 mm Hg), moderately hyperoxive (100-200 mm Hg), and severely hyperoxive (>200 mm Hg).

Sample size
The sample size was calculated to be a minimum of 60 patients, with 30 patients in each group, in order to achieve a test power of 80% at a confidence level of 95% and an effect size of f = 0.20 for repeated measures analysis.

Statistical analysis
Data are presented as mean and standard deviation or median, minimum, and maximum values.The normality of data was tested with the Shapiro-Wilk test.An independent-samples t test or a Mann-Whitney U test was used to compare the variables between the control and ORi group.
A repeated-measures ANOVA was used to assess the differences at different time points.Receiver operating characteristic (ROC) analysis was performed to determine the diagnostic performance of the test with the ORi parameter in identifying PaO 2 >150.Area under the curve (AUC), sensitivity, selectivity values, and cut-off values were calculated according to the Youden index.The Pearson correlation coefficient and significance tests were used to evaluate variable correlations.A Pearson χ 2 test was used to compare PaO 2 classifications between the groups.P < 0.05 was considered statistically significant.The analysis was performed with SPSS, version 22 (IBM Corp., Armonk, NY, USA).

Correlation between Ori and PaO 2
Across all time points and in all groups, there was a highly positive linear correlation between PaO 2 and ORi (r = 0.937; P < 0.001).A highly positive linear correlation was found between PaO 2 and ORi when data from each time point were analyzed (Table 2).Across all time points, there was a highly positive linear correlation between ORi and PaO 2 in both groups, with r The ability of Ori to predict hyperoxia (rOC curve) The use of ORi showed high diagnostic performance for PaO 2 >150 (P < 0.001; AUC = 0.983).The cut-off value for ORi was 0.225 according to the Youden index.The sensitivity and selectivity of the test were 94% and 94.9%, respectively (Supplemental Figure 1).

group comparison by PaO 2 values
Across all time points, PaO 2 was significantly higher in the control group than in the ORi+SPO 2 group (P < 0.001).The mean PaO 2 was 153.45 ± 46.736 in the control group and 117.85 ± 34.949 in the ORi+SPO 2 group.PaO 2 values were significantly lower in the ORi+SpO 2 group than in the control group at all time points after the 6th hour (Table 3).
An intragroup evaluation showed a significant difference between time points in the ORi+SpO 2 group (P < 0.001).While no difference was observed between the hours 30 and 36 and hours 42 and 48, a significant difference was observed between hours 0, 6, 12, 18, 24, and 30 (Table 3).
In the ORi+SpO 2 group, PaO 2 significantly decreased until the 30th hour, but thereafter there was no significant difference, and PaO 2 values were close to normoxemia (Figure 2).
In the control group, significant differences were observed between the hours 0 and 24, 30, 42, and 48, and between hours 6 and 30, and 42 and 48 (P = 0.025).There was no significant difference between hours 12, 18 30, 36, 42, and 48 time points (Figure 2).PaO 2 values did not significantly change in the control group and were higher than in the ORi+SpO 2 group (Table 3).

FiO 2 distribution of the groups (PaO 2 >120 mm Hg)
There was a significant difference in FiO 2 distributions between the groups (P < 0.001).When PaO 2 was greater than 120 mm Hg, FiO 2 within the 0.25-0.30range was observed in 38.9% of the ORi+SpO 2 group and 0% of the control group.FiO 2 greater than 0.40 was observed in 83.5% of the control group and in only 40% of the ORi+SpO 2 group.FiO 2 lower than 0.40 was observed in 60% of the ORi+SpO 2 group (Table 5).

Hemodynamic and other parameters
There was no significant difference between the groups in terms of MAP, HR, and PaCO 2 parameters (P > 0.05).In the control group, PEEP values were significantly lower, except at the 18-hour and 24-hour time points (Supplemental Table 1).

DiSCUSSiON
This randomized controlled study involving patients who received MV support in the ICU showed that: Oxygen is considered a drug and should be used judiciously in patients who require it, as it has no beneficial effect on mortality.For instance, routine supplemental oxygen use did not reduce mortality in patients with suspected myocardial infarction without hypoxemia (15).The Oxygen-ICU study revealed higher mortality in the conventional oxygen therapy group with high PaO 2 values compared with the conservative oxygen therapy group with low PaO 2 values (20.2% vs 11.6%) (16).Moreover, recent guidelines strongly advise against administering unnecessary oxygen therapy to non-hypoxemic patients with cardiac ischemia or stroke (17,18).To optimize oxygen therapy in the intensive care unit, the European Society of Intensive Care Medi-  www.cmj.hrcine recommends avoiding both hypoxemia and hyperoxemia in traumatic brain injury (TBI) patients.They suggest maintaining an optimal PaO 2 of 80-120 mm Hg (10-16 kPa) for TBI patients, with or without increased intracranial pressure, and issued the recommendation of general normoxemia, although specific PaO 2 targets may need to be tailored to the individual (19).The "normo-rule, " which emphasizes normo-thermia, normo-tension, normoxia, etc, also applies to oxygen therapy in the ICU.
Another question is whether adverse outcomes of hyperoxia are associated with high arterial peak oxygen levels or prolonged exposure to high PaO 2 .In a multicenter study of 14 441 ICU patients, exposure to both severe hyperoxia and prolonged exposure to mild and severe arterial hyperoxia were associated with adverse outcomes (4).Because ICU patients typically have a longer stay and therefore a higher potential risk of exposure to hyperoxia compared with the patients assessed in the intraoperative period, hyperoxia awareness and prevention in ICUs are extremely important.
Recent studies have suggested that the use of ORi, which can continuously and noninvasively measure oxygen levels, may effectively prevent hyperoxia (11,20).The number of studies investigating the effectiveness of ORi in preventing hyperoxia in the ICU is limited.One of the few studies on this topic reported that using ORi monitoring for FiO 2 titration significantly reduced hyperoxia exposure time compared with using SpO 2 alone.The study cited nurses' reluctance to reduce oxygen rates when SpO 2 was within the normal range as one reason for this (21).
Similar to previous studies, our study showed that using ORi and SpO  (22).
Awareness is another crucial factor in preventing hyperoxia.A study of Dutch clinicians' responses to hyperoxia in ventilated patients showed that if FiO 2 was <0.40, hyperoxia was accepted, without adjusting ventilation settings in 78% of the patients.Additionally, ventilation settings were not changed in 68% of patients with PaO 2 >120 mm Hg and FiO 2 >0.40 (2).In our study, 83.5% of the control group had PaO 2 >120 mm Hg and FiO 2 >0.40.Only 16.5% of the control group had FiO 2 <0.40, compared with 60% of the ORi+SpO 2 group.This difference may be due to the increased awareness of hyperoxia among clinicians and nurses who evaluated an additional parameter with SpO 2 when FiO 2 titration was guided by ORi+SpO 2 .Thus, using ORi+SpO 2 guidance for FiO 2 titration may be an effective approach to increase awareness and reduce the risk of hyperoxia in ICU patients.
Our study has several limitations.First, the design was limited to a single center, which may have affected the generalizability of the results.Second, the time intervals chosen for data collection could have been more frequent, which would have given us a better understanding of the changes in the data over time.Third, while we observed differences in PaO 2 values between the two groups, we did not measure oxidative stress indicators.Fourth, we excluded patients with impaired perfusion, but we did not record perfusion index values.Despite this, all ORi values were evaluated.Lastly, while differences in PEEP levels at some time points may be clinically insignificant, we did not assess their impact on PaO 2 values between the two groups.
Sarıtaş et al: Oxygen reserve index in the prevention of hyperoxia in critically ill patients on mechanical ventilation www.cmj.hr

FigUrE 1 .
FigUrE 1. Flowchart of the study.
(I) there was a very strong positive linear relationship between ORi and PaO 2 , indicating ORi's effectiveness in detecting hyperoxia; (II) FiO 2 titration under the guidance of ORi and SpO 2 together effectively reduced PaO 2 values; and (III) ORi could play a role in providing optimum oxygenation by protecting the patient from severe hyperoxia and increasing the clinician's awareness.

FigUrE 3 .*
FigUrE 3. Correlation between oxygen reserve index (Ori) and fraction of inspired oxygen (FiO 2 ) in partial pressure of oxygen (PaO 2 ) categories classified by group and timepoint.

TAbLE 1 .
Demographic characteristics of the patients
2 guidance to titrate FiO 2 resulted in lower PaO 2 values compared with the control group.We observed significantly lower PaO 2 values in the ORi+SpO 2 group compared with the control group after the 6th hour.This reduced the time of exposure to high arterial oxygen levels.ORi+SpO 2 group (45.6% vs 8.9%).FiO 2 titration guided by the combination of ORi and SpO 2 follows the desired "normo" rule in ICUs.In agreement with the results of our study, Ahn et al reported that ORi and SpO 2guided FiO 2 titration decreased PaO 2 level and the incidence of hyperoxemia